Project Summary/Abstract This application aims to elucidate the molecular mechanisms of alveolar formation during development and in response to lung injury. We anticipate that our study will provide new insight into the pathogenesis of human lung diseases caused by the failure of alveolar development or regeneration, notably bronchopulmonary dysplasia (BPD) and chronic obstructive lung disease (COPD), respectively. In preliminary studies, we have discovered a critical role of planar cell polarity (PCP) in controlling alveolar formation. In this proposal, we aim to test how PCP signaling mediates cell-cell interactions between alveolar cells and mesenchymal myofibroblasts, leading to PDGF signaling, cell shape changes and alveolar formation. Our specific aims are: (1) To test the hypothesis that Vangl2-mediated planar cell polarity is required for PDGF signaling and cell shape changes during alveolar formation in development; (2) To test the hypothesis that a Wnt5a-Vangl2 axis controls alveolar formation; and (3) To molecularly characterize realveolarization following lung injury in adults. Taken together, these studies will increase our mechanistic understanding of alveolar formation during development and following lung injury and facilitate future diagnosis and treatment of lung diseases caused by loss of alveoli.